Kinase inhibitors have demonstrated great promise for the treatment of some types of cancer, such as leukemia and a few solid tumors. Will kinase inhibitors have a more general role in cancer therapy? Glioblastoma, the most common malignant primary brain tumor of adults and one of the most lethal of all cancers, represents an ideal clinical model to address this question. Chronic PI3K/Akt pathway activation promotes malignant transformation and tumor progression in pre-clinical glioblastoma models, and is commonly detected in glioblastoma patient samples. However, clinical application of PI3K/Akt pathway inhibitors has been severely limited by an inability to determine which patient is most likely to benefit. Because morphologically indistinguishable glioblastomas can have distinct classes of causal oncogene/signaling pathway activation that may render them differentially sensitive to kinase inhibitors, it is crucial to develop methods of detecting pathway activation. Our laboratory has developed a method of analyzing PI3K/Akt pathway activation in routinely processed glioblastoma patient biopsies, which may potentially be used to determine which patients are most likely to benefit from kinase inhibitor therapy (Choe et al., 2003), and we have become a molecular correlates analysis center for a number of ongoing, investigator-initiated multi-center clinical trials of targeted pathway inhibitors. This proposal will provide us with a unique opportunity to determine the impact of chronic PI3K pathway activation on patient survival, to determine whether PI3K pathway activation can be used to select patients for targeted inhibitor therapy, and to develop surrogate molecular markers that can be used to detect pathway inhibition and predict response in patients in molecularly-based clinical trials.